The goal of the present study is to develop a targeted delivery system for the transfer of DNA into mammalian cells using a DNA binding protein in combination with a cell binding protein. A fusion protein was constructed with transforming growth factor alpha (TGFa) at the N-terminus and human telomeric DNA binding protein (hTRF) at the C-terminus. This bifunctional protein was expressed in E.coli and partially purified. Binding activity to human telomeric DNA sequences (T2AG3 repeats) was tested by gel shift assay and was evident with 10-100 ng of protein. TGFa binding activity to the epidermal growth factor (EGF) receptor was demonstrated indirectly by the ability of the bifunctional protein to block the cell killing activity of TGFa-toxin in cell lines expressing the EGF receptor. Current work focuses on the receptor-mediated uptake of the DNA/protein complexes in cell lines expressing EGF receptors. Plasmid DNA containing T2AG3 repeats and the hygromycin-resistance gene or the E. coli Lac Z (beta-gal) marker gene will be bound to the fusion protein and added to cells. Delivery efficiency will be assessed by the number of hygromycin-resistant colonies or beta-gal expressing cells. If the delivery of a telomeric DNA plasmid is successful, this strategy will be extended to the delivery of high molecular weight DNA vectors containing telomeric DNA.